Abstract
Brain malformations causing various neurological deficits are being recognized as a significant public health concern and are the subject of growing etio-pathological interest. In isolation or associated with extracerebral anomalies, they belong to the vast spectrum of embryofetal disorders (birth defects), which are nowadays a prevalent cause of neonatal and pediatric mortality and morbidity in developed countries. However, most remain unexplained and treatments or preventive measures are scarce. Usually, brain malformations, resulting from chromosomal/genetic mutations or disruption, are only documented from a clinical and a radiological point of view and named by morphological descriptive terms.
To further refine the characterization of brain malformations, neurohistopathological studies have emerged as a powerful tool. Embryofetal and neuropathological studies performed after fetal death or termination of pregnancy have demonstrated a positive impact of such necropsy-based studies on the identification of the pathogenesis of brain malformations, in addition to illustrating their phenotypic diversity and revealing genetic heterogeneity (i.e., genocopies). Indeed, the new-generation DNA sequencing techniques permit identification of a growing number of genetic variations. Interestingly, functional studies reveal involvement of these genes in distinct biological processes and molecular pathways. Dissection of molecular cascades of signaling pathways using genotype/phenotype correlations demonstrates that mutations in different genes involved in a common signaling pathway may result in overlapping patterns of malformation. Furthermore, signaling pathways may be a possible target of exogenous agents, which will phenocopy genetic causes. Thus, signaling pathways have emerged as key modulators of phenotypic diversity. Integration of these important findings opens a new way in the evaluation of malformations, based on functional disorders, such as ciliopathies, tubulinopathies, dystroglycanopathies, mTOR pathway disorders, etc. This new approach ends the classical dogma of one gene/one disease and improves our understanding of the genetic and phenotypic heterogeneity of birth defects.
The time in development at which the insult occurs is determinant in the final morphology of the malformation and genetic causes as well as teratogens may produce similar anomalies. M. G. Noman
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Encha-Razavi F, Gonzalès M, Laquerrière A, Martinovic J, Sinico M, Allias F, et al. A practical approach to the examination of the malformed fetal brain: impact on genetic counselling. Pathology. 2008;40:180–7.
Herion NJ, Salbaum JM, Kappen C. Traffic jam in the primitive streak: the role of defective mesoderm migration in birth defects. Birth Defects Res A Clin Mol Teratol. 2014;100:608–22.
Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome? Trends Genet. 2009;25:501–10.
Chavali PL, Pütz M, Gergely F. Small organelle, big responsibility: the role of centrosomes in development and disease. Phil Trans R Soc B 2014;369:20130468.
Mirzaa GM, Poduri A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am J Med Genet C Semin Med Genet. 2014;166C:156–72.
Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:52–61.
Richards LJ, Plachez C, Ren T. Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin Genet. 2004;66:276–89.
Putoux A, Thomas S, Coene KL, Davis EE, Alanay Y, Ogur G, et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011;43:601–6.
Jiménez AJ, Domínguez-Pinos MD, Guerra MM, Fernández-Llebrez P, Pérez-Fígares JM. Structure and function of the ependymal barrier and diseases associated with ependyma disruption. Tissue Barriers. 2014;2:e28426.
Viot G, Sonigo P, Simon I, Simon-Bouy B, Chadeyron F, Beldjord C, Tantau J, et al. Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. Am J Med Genet A. 2004;126A:123–8.
Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol. 2002;51:340–9.
Devisme L, Bouchet C, Gonzalès M, Alanio E, Bazin A, Bessières B, et al. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain. 2012;135:469–82.
Vuillaumier-Barrot S, Bouchet-Séraphin C, Chelbi M, Devisme L, Quentin S, Gazal S, et al. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. Am J Hum Genet. 2012;9:1135–43.
Ostrovskaya TI, Lazjuk GI. Cerebral abnormalities in the Neu-Laxova syndrome. Am J Med Genet. 1988;30:747–56.
Encha Razavi F, Larroche JC, Roume J, Gonzales M, Kondo HC, Mulliez N. Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome. Am J Med Genet. 1996;62:16–22.
Martynoga B, Drechsel D, Guillemot F. Molecular control of neurogenesis: a view from the mammalian cerebral cortex. Cold Spring Harb Perspect Biol. 2012;4:10. pii: a008359.
Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, et al. Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. Acta Neuropathol Commun. 2014;2:69.
Judkins AR, Martinez D, Ferreira P, Dobyns WB, Golden JA. Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal cortical laminar organization. J Neuropathol Exp Neurol. 2011;70:438–43.
Stutterd CA, Leventer RJ. Polymicrogyria: a common and heterogeneous malformation of cortical development. Am J Med Genet C Semin Med Genet. 2014;166C:227–39.
Adle-Biassette H, Saugier-Veber P, Fallet-Bianco C, Delezoide AL, Razavi F, Drouot N, et al. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. Acta Neuropathol. 2013;126:427–42.
Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet. 2014;133:367–77.
Michaud J, Mizrahi EM, Urich H. Agenesis of the vermis with fusion of the cerebellar hemispheres, septo-optic dysplasia and associated anomalies. Report of a case. Acta Neuropathol. 1982;56:161–6.
Pasquier L, Marcorelles P, Loget P, Pelluard F, Carles D, Perez MJ, et al. Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases. Acta Neuropathol. 2009;117:185–200.
Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis. 2011;6:50.
Mahieu-Caputo D, Salomon LJ, Dommergues M, Aubry MC, Sonigo P, Martinovic Y, et al. Arthrogryposis multiplex congenita and cerebellopontine ischemic lesions in sibs: recurrence of prenatal disruptive brain lesions with different patterns of expression? Fetal Diagn Ther. 2002;17:153–6.
Bessières-Grattagliano B, Foliguet B, Devisme L, Loeuillet L, Marcorelles P, Bonnière M, et al. Refining the clinicopathological pattern of cerebral proliferative glomeruloid vasculopathy (Fowler syndrome): report of 16 fetal cases. Eur J Med Genet. 2009;52:386–92.
Thomas S, Encha-Razavi F, Devisme L, Etchevers H, Bessieres-Grattagliano B, Goudefroye G, et al. High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy. Hum Mutat. 2010;31:1134–41.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing
About this chapter
Cite this chapter
Encha-Razavi, F. (2015). Brain Malformations. In: Khong, T.Y., Malcomson, R.D.G. (eds) Keeling’s Fetal and Neonatal Pathology. Springer, Cham. https://doi.org/10.1007/978-3-319-19207-9_27
Download citation
DOI: https://doi.org/10.1007/978-3-319-19207-9_27
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-19206-2
Online ISBN: 978-3-319-19207-9
eBook Packages: MedicineMedicine (R0)